Azacitidine and Entinostat in Treating Patients With Metastatic Colorectal Cancer

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01105377
First received: April 15, 2010
Last updated: August 29, 2013
Last verified: August 2013
  Purpose

This phase II trial is studying how well giving azacitidine together with entinostat works in treating patients with metastatic colorectal cancer. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving azacitidine together with entinostat may kill more tumor cells


Condition Intervention Phase
Recurrent Colon Cancer
Recurrent Rectal Cancer
Stage IV Colon Cancer
Stage IV Rectal Cancer
Drug: entinostat
Drug: azacitidine
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Study of Azacitidine and Entinostat in Patients With Metastatic Colorectal Cancer

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Confirmed Tumor Response [ Time Frame: At 6 month evaluation ] [ Designated as safety issue: No ]
    Each evaluable patient is classified as having a confirmed tumor response if they have either a complete response (CR) or partial response (PR) lasts at least 4 weeks. Tumor response is measured by using RECIST v1.1 (Response Evaluation Criteria in Solid Tumors). A CR is defined as a disappearance of all target lesions, and each target lymph node must have reduction in short axis to <1.0 cm. A PR is defined as a 30% decrease in the sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation, compared to pre-treatment measurements. The confirmed response rate is calculated as the number of confirmed CR+PR, divided by the total number of evaluable patients, with 95% confidence intervals estimated using the approach of Duffy and Santner.


Secondary Outcome Measures:
  • Time to Progression [ Time Frame: From the start of treatment to the earliest of the date documenting disease progression, assessed up to 3 years ] [ Designated as safety issue: No ]
    Time to disease progression (TTP) is defined as the time from the start of treatment to the earliest of the date documenting disease progression or most recent assessment for patients having no progression. The distribution of TTP is estimated using the method of Kaplan-Meier.


Enrollment: 47
Study Start Date: April 2010
Study Completion Date: June 2013
Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (entinostat, azacitidine)
Patients receive 40 mg/m^2 azacitidine subcutaneously on days 1-5 and 8-10 and 7 mg oral entinostat on days 3 and 10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: entinostat
Seven mg given orally on days 3 and 10 of a 28-day cycle
Other Names:
  • HDAC inhibitor SNDX-275
  • SNDX-275
Drug: azacitidine
On days 1-5 and 8-10 of a 28-day cycle, 40 mg/m^2 are given subcutaneously.
Other Names:
  • 5-AC
  • 5-azacytidine
  • azacytidine
  • Vidaza

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the preliminary efficacy via Response Evaluation Criteria In Solid Tumors (RECIST) response rate of the combination of azacitidine and entinostat in patients with metastatic colorectal cancer.

SECONDARY OBJECTIVES:

I. Explore the effects of azacitidine and entinostat on time to progression in patients with metastatic colorectal cancer.

II. To assess the toxicity for combination azacitidine and entinostat therapy.

OUTLINE: This is a multicenter study.

Patients receive azacitidine subcutaneously on days 1-5 and 8-10 and oral entinostat on days 3 and 10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Blood and tumor tissue samples are collected at baseline and periodically during courses 1-3 for DNA methylation, histone deacetylation activity, and acetylation of H3 and H4 histones analysis by polymerase chain reaction (PCR), western blot, and RT-PCR assays. Pharmacogenomic studies may also be conducted.

After completion of study therapy, patients are followed up every 3-6 months for up to 3 years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed metastatic colorectal cancer
  • Measurable disease
  • For Cohort I only (See Participation Flow section for details):

    • Must have failed ≥2 prior chemotherapy regimens.
  • For Cohort II only (See Participation Flow section for details):

    • Must have failed no more than 2 prior chemotherapy regimens in the metastatic setting if KRAS mutation positive OR no more than 3 prior regimens in the metastatic setting if Kirsten rat sarcoma (KRAS) wild-type (with one of those regimens being an anti-epidermal growth factor (anti-EGF). Failure is defined as progression while on treatment. Maintenance therapy is considered part of the previous regimen.
  • For Cohort II only (See Participation Flow section for details):

    • Liver disease burden limited to no more than 30% of total liver volume as assessed through liver volumetric assessment on scan by central radiologist review. NOTE: If patient has no liver disease, the patient may be registered without waiting for confirmation from the central radiology review. Submission of scans for measurements of tumor burden in liver to central radiologist.
  • Not a candidate for curative resection
  • No central nervous system (CNS) metastases within ≤ 2 years

    • Treatment for brain metastasis and whole brain disease that has remained stable for > 3 months allowed
    • Patients who have not been treated with steroid therapy may be allowed
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Life expectancy ≥ 12 weeks
  • Leukocytes ≥ 3,000/mm^3
  • Absolute neutrophil count (ANC) ≥ 1,500/mm^3
  • Platelet count ≥ 100,000/mm^3
  • Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times ULN
  • Creatinine normal OR creatinine clearance ≥ 60 mL/min
  • Negative pregnancy test
  • Not pregnant or nursing
  • Fertile patients must use effective contraception
  • Sensory neuropathy ≤ grade 2 allowed
  • Willing to provide tissue and blood samples
  • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to entinostat, azacitidine, mannitol, or other agents used in the study
  • No uncontrolled intercurrent illness including, but not limited to, any of the following:

    • Ongoing or active infection
    • New York Heart Association (NYHA) class II-IV symptomatic congestive heart failure
    • Unstable angina pectoris
    • Cardiac arrhythmia
    • Psychiatric illness and/or social situations that would limit compliance with study requirements
  • No history of severe bleeding without thrombocytopenia
  • No concurrent radiotherapy including palliative treatment
  • Toxicities from prior therapy have resolved to ≤ grade 1
  • More than 4 weeks since prior chemotherapy (> 6 weeks for nitrosoureas or mitomycin C)
  • More than 4 weeks since prior major surgical procedure
  • No prior histone deacetylase inhibitors (including valproic acid) or demethylating agents
  • No concurrent investigational agents
  • No concurrent combination antiretroviral therapy in HIV-positive patients
  • No concurrent investigational or commercial anticancer agents or therapies
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01105377

Locations
United States, Arizona
Mayo Clinic in Arizona
Scottsdale, Arizona, United States, 85259
United States, California
University of Southern California
Los Angeles, California, United States, 90033-0804
United States, Florida
Mayo Clinic in Florida
Jacksonville, Florida, United States, 32224-9980
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287-8936
United States, Michigan
Wayne State University
Detroit, Michigan, United States, 48202
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Metro-Minnesota CCOP
Saint Louis Park, Minnesota, United States, 55416
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, Pennsylvania
University of Pittsburgh Cancer Institute
Pittsburgh, Pennsylvania, United States, 15232
United States, Wisconsin
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
Investigators
Principal Investigator: Nilofer Azad Mayo Clinic
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01105377     History of Changes
Other Study ID Numbers: NCI-2010-02024, MC084B, N01CM62209, N01CM62205, CDR0000670136
Study First Received: April 15, 2010
Results First Received: August 29, 2013
Last Updated: August 29, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Colonic Neoplasms
Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Azacitidine
Histone Deacetylase Inhibitors
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors

ClinicalTrials.gov processed this record on April 17, 2014